Національний медичний університет імені О.О.Богомольця

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Ministry of Public Health of Ukraine

National O.O.Bohomolets Medical University

Oncology Department

Study Guide

of the Lecture Course “Oncology”

Part III

For the students of medical faculties

Worked out by I.B.Shchepotin MD, PhD, DSci, Prof; G.A.Vakulenko MD, PhD, DSci, Prof; V.E.Cheshuk MD, PhD, DSci; A.S.Zotov MD, PhD; O.I.Sidorchuk MD, PhD; V.V.Zaychuk MD, PhD; L.V.Grivkova MD, PhD; O.E.Lobanova MD; I.N.Motuzyuk MD; Y.V.Levchishin MD.

Kyiv - 2008

Ministry of Public Health of Ukraine

National O.O.Bohomolets Medical University

Oncology Department

“APPROVED”

Vice-Rector for Educational Affairs

Professor O. Yavorovskiy

______________

“___” __________ 2008

Study Guide

of the Lecture Course “Oncology”

Part III

For the students of medical faculties

Worked out by I.B.Shchepotin MD, PhD, DSci, Prof; G.A.Vakulenko MD, PhD, DSci, Prof; V.E.Cheshuk MD, PhD, DSci; A.S.Zotov MD, PhD; O.I.Sidorchuk MD, PhD; V.V.Zaychuk MD, PhD; L.V.Grivkova MD, PhD; O.E.Lobanova MD; I.N.Motuzyuk MD; Y.V.Levchishin MD.

Kyiv - 2008

The texts of the lectures are approved by the methodical counsel

of Oncology Department.

Protocol № 19 « 17 » march 2008.

CONTENTS

Lecture 12

Tumors of the soft tissue

Lecture 13

Skin cancer

Lecture 14

Melanoma

Lecture 15

Cervical cancer

Lecture 16

Ovarian cancer

Lecture 17

Uterine cancer

Literature

Lecture 12

Tumors of the soft tissue

Sarcomas are malignant (cancerous) tumors that develop in tissues which connect, support, or surround other structures and organs of the body. In general, soft tissue sarcomas do not seem to result from malignant changes or the dedifferentiation of benign soft tissue tumors, and despite the variety of histologic subtypes, soft tissue sarcomas have many clinical and pathologic features in common. The dominant pattern of metastasis is hematogenous. Lymph node metastasis is rare (less than 5%).

Soft tissue sarcomas are rare. These neoplasm's constitute only 0,2-2,6% of the malignant tumors and affect almost equal often men and women, more common in the age of 20-50 years. However, sarcomas occur more often in children and young adults.

Soft tissue sarcomas can arise almost anywhere in the body: muscles, tendons, fibrous tissues, fat, blood vessels, nerves, and synovial tissues are types of soft tissue. About 55% to 60% percent occur in the extremities (e.g., arms, legs); the rest begin in the trunk (15% to 20%), head and neck area (8% to 10%), internal organs, or the retroperitoneum (15%).

Some conditions of soft tissues are caused by inflammation or injury and can form a mass that looks like a soft tissue tumor. Unlike a true tumor, they do not come from a single abnormal cell, they have limited capacity to grow or spread to nearby tissues, and never spread through the bloodstream or lymph system. Examples include nodular fasciitis and myositis ossificans, which involve tissues under the skin and muscle tissues, respectively. Although most soft tissue sarcomas do not have a clearly defined cause, researchers have identified several factors that increase the likelihood of developing these tumors. External radiation therapy is a well-established risk factor for soft tissue sarcoma, as shown by the fact that the incidence of sarcomas is increased eightfold to 50-fold in patients treated with radiation therapy for cancer. The risk appears to be related to the dose of radiation.

Another risk factor for soft tissue sarcomas is exposure to certain chemicals in the workplace, including vinyl chloride, arsenic, herbicides such as phenoxyacetic acids, and wood preservatives that contain chlorophenols. Chronic lymphedema (a condition in which excess fluid collects in the tissue and causes swelling) following radiation to, or surgical removal of, lymph nodes is also a risk factor.

Specific inherited genetic alterations are associated with an increased risk of both bone and soft tissue sarcomas. The oncogenes (ie, genes that can induce malignant transformation and tend to drive cells toward proliferation) that have been implicated in the development of soft tissue sarcomas include MDM2, N-myc, c-erbB2, and members of the ras family. Amplification of these genes in several subtypes of soft tissue sarcomas has been shown to correlate with an adverse outcome. Cytogenetic analysis of soft tissue tumors has also identified distinct chromosomal translocations that code for oncoproteins associated with certain histologic subtypes. The best characterized gene rearrangements have been found in Ewing’s sarcoma (EWS–FLI-1 fusion), clear-cell sarcoma (EWS–ATF1 fusion), myxoid liposarcoma (TLS–CHOP fusion), alveolar rhabdomyosarcoma (PAX3–FHKR fusion), desmoplastic small round-cell tumor (EWS–WT1 fusion), and synovial sarcoma (SSX–SYT fusion). Tumor suppressor genes play a critical role in cell growth inhibition and can suppress the growth of cancer cells. However, these genes can be inactivated by hereditary or sporadic mechanisms. Two such genes that are particularly relevant to soft tissue tumors are the retinoblastoma (Rb) gene and the p53 tumor suppressor gene. Mutations or deletions in the Rb gene can lead to the development of retinoblastomas and sarcomas of the soft tissue and bone. In addition, although mutations in the p53 tumor suppressor gene are the most common mutations in human solid tumors, they have also been observed in 30% to 60% of soft tissue sarcomas. There is also a high incidence of soft tissue sarcomas in patients with germline mutations in the tumor suppressor gene p53 (ie, the Li-Fraumeni syndrome).

Certain inherited diseases are associated with an increased risk of developing soft tissue sarcomas. Studies have focused on genetic changes that may lead to the development of soft tissue sarcomas. For example, people with von Recklinghausen’s disease (also called neurofibromatosis type 1 and associated with alterations in the NF1 gene), hereditary leiomyomatosis and renal cell cancer syndrome (with alterations in the FH gene), and hereditary retinoblastoma (with alterations in the RB1 gene) are at increased risk of developing soft tissue sarcomas.

Kaposi’s sarcoma is a soft tissue sarcoma that sometimes develops in people with human immunodeficiency virus (HIV) infection. The primary cause of Kaposi’s sarcoma is infection with Kaposi sarcoma-associated herpesvirus (KSHV), or human herpesvirus 8. However, people infected with KSHV, but not HIV, rarely develop Kaposi’s sarcoma.

Soft tissue sarcomas are grouped together because they share certain microscopic characteristics, have similar symptoms, and are generally treated in similar ways. They are usually named for the type of tissue in which they begin. There are many types of soft tissue tumors, and not all of them are cancerous. There are about 50 different types of soft tissue sarcomas.

Histological classification on the soft tissue tumors (WHO 1998)

Grading of bone tumors is roughly based on the cellularity of the lesion compared to the amount of extra cellular matrix, nuclear features, the presence of mitotic figures and necrosis. Staging via the TNM system is normally not used, because metastases in lymph nodes are not frequent in these lesions. Therefore staging is based on degree of differentiation of the tumor tissue and local and distant spread of the tumor.

I. Tumors and tumor-like lesions of the fibrous tissue.

А. Benignant: Fibromas: 1. Solid fibroma; 2. Soft fibroma (fibromyoma); 3. Dermatofibroma (Fibrous histiocytoma ); 4. Elastofibroma of the back.

B. Benignant: Fibromatosis : 1. Scar fibromatosis; 2. Keloid; 3. Fasciitis nodular; 4. Radiation fibromatosis; 5. Juvenile hyaline fibromatosis ; 6. Abdominal fibromatosis (abdominal desmoid); 7. Aggressive fibromatosis (nonabdominal desmoid); 8. Congenital fibromatosis.

C. Malignant: 1. Fibrosarcoma.

II. Fat tissue tumors.

А. Benignant: 1. Lipoma (including fibrolipoma, angiolipoma etc.); 2. Intermuscular lipoma; 3. Hibernoma; 4. Angiomyolipoma; 5. Lipoblastomatosis; 6. Diffuse lipomatosis.

Б. Malignant: 1. Liposarcoma.

III. Muscular tissue tumors

А. Smooth muscle tumors.

1. Benignant: а) Leiomyoma; б) angiomyoma; в) leiomyoblastoma.

2. Malignant: а) Leiomyosarcoma .

B. Striated muscle tumors.

1. Benignant: а) Rhabdomyoma ;

2. Malignant: а) Rhabdomyosarcoma .

IV. Blood vessels tumors.

А. Benignant.

1. Hemangioma : а) hemangioendothelioma benignant; b) capillary hemangioma; c) cavernous; d) venous.

2. Intermuscular hemangioma (capillary, cavernous, arterio-venous);

3. System hemangiomatosis;

4. Hemangiomatosis with/without congenital arterio-venous fistula;

5. Hemangiopericytoma benignant, b) glomus tumor.

7. Angiolipoma.

В. Malignant.

1. Hemangioendothelioma malignant (angiosarcoma);

2. Hemangiopericytoma malignant.

V. Lymphatic vessels tumors.

А. Benignant.

1. lymphangioma: а) capillary; b) cavernous: c) cystic;

2. Lymphangiomyoma;

3. System lymphangiomyomatosis .

B. Malignant.

1. Lymphangioendothelioma malignant (lymphangiosarcoma);

VI. Synovial tissue tumors.

А. Benignant.

1. Benignant synovioma.

B. Malignant.

1. Synovial sarcoma.

VII. Mesothelial tissue tumors .

А. Benignant mesothelioma .

B. Malignant mesothelioma .

VIII. The tumors of the peripheral nerves.

А. Benignant.

1. Traumatic neuroma;

2. Neurofibroma;

3. Neurilemmoma (schwannoma );

4. Neurofibromatosis.

B. Malignant.

1. Malignant schwannoma (neurofibrosarcoma);

2. Primitive neuroectodermal tumor (peripheral neuroepitelioma PNET).

IX. Tumors of the sympatic ganglia.

А. Benignant. 1. Ganglioneuroma.

B. Malignant. 1. Neuroblastoma, ganglioneuroblastoma.

Х. Tumors of the paraganglious stuctures.

А. Pheochromocytoma: 1. Benignant; 2. Malignant.

B. Chemodectoma: 1. Benignant; 2. Malignant.

C. Nonclassified paraganglioma.

XI. Plurypotential mesenchymal tumors

А. Benignant: mesenchymoma.

B. Malignant : Malignant mesenchymoma.

ХII. Tumors of the possible extragenital origin.

А. Benignant. 1. Teratoblastoma.

B. Malignant.

1. Teratocarcinoma;

2. Embrional carcinoma.

XIII. Tumor with nonelucidated hystogenesis.

А. Benignant.

1. Granular cell tumor;

3. Soft tissue osteoma;

4. Myxoma.

2. Soft tissue chondroma;

B. Malignant.

1. Alveolar soft part sarcoma ;

2. Malignant granular cell tumor ;

3. Chondrosarcoma extraskeletal;

4. Osteosarcoma extrasceletal;

5. Malignant giant cell tumor of soft tissue/soft parts;

6. Malignant fibroxanthoma;

7. Kaposi's sarcoma ;

8. Giant cell tumor of tendon sheath.

ХIV. Nontumorous or tumor-like lesions of the soft tissue.

А. Xanthomas.

B. Ganglia.

C. Myositis ossi´ficans.

D. Proliferative myositis.

ХV. Nonclassified tumors of the soft tissue.

Tumors of Fat Tissue:

Lipomas are benign tumors of fat tissue. They are the most common benign soft tissue tumor. Most are found under the skin, but they can develop anywhere in the body.

Lipoblastomas are benign fat tumors that occur in infants and young children.

Hibernomas, like lipomas, are also benign fat tissue tumors. They are much less common than lipomas.

Liposarcomas are malignant tumors of fat tissue. They can develop anywhere in the body, but they most often develop in the thigh, behind the knee, and inside the back of the abdomen. They occur mostly in adults between 50 and 65 years old. Some liposarcomas grow very slowly, whereas others can grow quickly. Your doctor can tell you which kind you have.

Tumors of Muscle Tissue

The human body has 2 types of muscle: smooth and skeletal.

• Smooth muscle is found in our internal organs such as stomach, intestines, blood vessels, or uterus (womb) and causes them to contract. These muscles are involuntary - that is, we don't control their movement.

• Skeletal muscle is sometimes called striated (because stripes can be seen inside the cells under the microscope). This is the muscle that allows us to move our arms and legs and other body parts when we want them to move -- that is, voluntary movement.

Smooth muscle sarcomas

Leiomyomas are benign tumors of smooth muscle (or involuntary muscle). Leiomyomas can arise almost anywhere in the body in either men or women because they can start in tissues as widespread, for example, as blood vessels or intestine. The most common of these is the fibroid tumor that develops in many women. It is really a leiomyoma of the uterus.

Leiomyosarcomas are malignant tumors of involuntary muscle tissue. They can grow almost anywhere in the body but are most often found in the retroperitoneum and the internal organs and blood vessels where leiomyomas also arise. Less often, they develop in the deep soft tissues of the legs or arms. They tend to occur in adults, particularly the elderly.

Skeletal muscle sarcomas

Rhabdomyomas are benign tumors of skeletal muscle (the muscle that is attached to bone and helps us to move). They are rare.

Rhabdomyosarcomas are malignant tumors of skeletal muscle. These tumors commonly grow in the arms or legs, but they can also begin in the head and neck area and in reproductive and urinary organs such as the vagina or bladder. Children are affected much more often than adults.

Tumors of Peripheral Nerve Tissue

Nerves run throughout the body. The brain and spinal cord are also considered central nerve tissue. The tumors discussed here are tumors of the nerves that run throughout the body, but not the brain or spinal cord.

Neurofibromas, schwannomas (neurilemoma), and neuromas are all benign tumors of nerves. These tumors can occur almost anywhere in the body. An inherited condition called neurofibromatosis or von Recklinghausen disease causes people to develop many neurofibromas throughout their body. Some of these, if they formed from very large nerves such as those in the upper arms or neck, can become malignant.

Malignant schwannomas, neurofibrosarcomas, or neurogenic sarcomas are malignant tumors of the cells that surround a nerve. A new name for these is malignant peripheral nerve sheath tumors.

Tumors of Joint Tissue

All of our joints are surrounded by tough tissue called synovium, which produces the fluid that lubricates the joint surfaces so that they move smoothly. Tumors of joints start in the synovium.

Nodular tenosynovitis is a benign tumor of joint tissue. It is most common in the hands and is more common in women than in men.

Synovial sarcoma is a malignant tumor of the tissue around joints. The most common locations are the knee and ankle. Other sites are the shoulder and hip. It tends to occur mostly in children and young adults, but can also occur in older people.

Tumors of Blood Vessels and Lymph Vessels

Hemangiomas are benign tumors of blood vessels. They are rather common, are often present at birth, and can affect the skin or internal organs. They sometimes disappear without treatment.

Glomus tumors are benign perivascular (around blood vessels) tumors. They usually are found under the skin of the fingers.

Hemangiopericytoma is a tumor of perivascular tissue. It most often develops in the legs, pelvis, and retroperitoneum (the back of the abdominal cavity). It is most common in adults. These can be either benign or malignant. They don’t often spread to distant sites, but tend to come back where they started, even after surgery.

Hemangioendothelioma is a blood vessel tumor that is less aggressive than hemangiosarcoma but still considered a low-grade cancer. It usually invades nearby tissues and sometimes can spread to distant parts of the body (metastasize). It may develop in soft tissues or in internal organs, such as the liver or lungs.

Angiosarcomas are malignant tumors that can develop either from blood vessels (hemangiosarcomas) or from lymph vessels (lymphangiosarcomas). These tumors can sometimes develop in a part of the body that has been exposed to radiation. Angiosarcomas are sometimes seen in the breast after radiation therapy for breast cancer or in the arm on the same side as a breast that has been irradiated or removed by mastectomy.

Kaposi sarcoma is a tumor formed by cells similar to those lining blood or lymph vessels. It is most common in people with human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS), but it can also develop in organ transplant patients who are taking medication to suppress their immune system. It is probably related to infection with a virus called human herpesvirus-8 (HHV-8).

Lymphangiomas are benign lymph vessel tumors that are usually present at birth. Lymph is a type of fluid that circulates in every tissue of the body, ending up in the venous system. It contains waste products from tissues and immune system cells. Lymphangiosarcomas are the malignant lymph vessel form of angiosarcomas.

Tumors of Fibrous Tissue

Fibrous tissue forms tendons and ligaments and covers bones as well as other organs in the body.

Fibromas, elastofibromas, superficial fibromatosis, and fibrous histiocytomas are all benign tumors.

Fibrosarcoma is cancer of fibrous tissue. It usually affects the legs, arms, or trunk. It is most common between the ages of 20 and 60, but can occur at any age, even in infancy.

Fibromatosis is the name given to fibrous tissue tumor with features in between fibrosarcoma and benign tumors such as fibromas and superficial fibromatosis. They tend to grow slowly but, often, steadily. At one time they were called desmoid tumors, when they were closely attached to skeletal muscles. Now they are called musculoaponeurotic fibromatosis. They do not metastasize, but they can invade nearby tissues and are sometimes fatal. Some doctors consider these to be a type of low-grade fibrosarcoma; others believe they are a unique type of fibrous tissue tumors. Certain hormones, particularly estrogen, increase the growth of some desmoid tumors. Antiestrogen drugs are sometimes useful in treating desmoids that cannot be completely removed by surgery.

Dermatofibrosarcoma protuberans (DFSP) is a slow-growing cancer of the fibrous tissue beneath the skin, usually in the trunk or limbs. It invades nearby tissues but rarely metastasizes.

Malignant fibrous histiocytoma (MFH) is most often found in the arms or legs. Less often, it can develop inside the back of the abdomen. This sarcoma is most common in older adults. Although it mostly tends to grow locally, it can spread to distant sites.

Tumors of Uncertain Tissue Type

Through microscopic examination and other laboratory tests, doctors can usually find similarities between most sarcomas and certain types of normal soft tissues. However, some sarcomas have not been linked to a specific type of normal soft tissue.

Myxoma is a benign tumor that usually is located in muscles but does not develop from muscle cells. The cells of a myxoma produce mucus-like material, a feature that distinguishes this tumor. It almost always occurs in adults.

Granular cell tumors are usually benign tumors of adults that occur often in the tongue but can be found almost anywhere in the body.

Malignant mesenchymoma is a rare type of sarcoma that contains some areas showing features of fibrosarcoma and other areas with features of at least two other types of sarcoma.

Alveolar soft-part sarcoma is a rare cancer that mostly affects young adults. The legs are the most common location of these tumors.

Epithelioid sarcoma most often develops in tissues under the skin of the hands, forearms, feet, or lower legs. Adolescents and young adults are often affected.

Clear cell sarcoma is a rare cancer that often develops in tendons of the arms or legs. Under the microscope, it shares some features with malignant melanoma, a type of cancer that develops from pigment-producing skin cells. How cancers with these features develop in parts of the body other than the skin is not known.

Desmoplastic small cell tumor is a rare sarcoma of adolescents and young adults, found most often in the abdomen. Its name means that it is formed by small, round cancer cells surrounded by scar-like tissue.

Other Types of Sarcoma

There are other types of tumors called soft tissue sarcomas, however, these are all quite rare.

Clinical Presentation

Soft tissue sarcomas usually appear as a lump or mass, but they rarely cause pain, swelling, or other symptoms. A lump or mass might not be a sarcoma; it could be benign, a different type of cancer, or another problem. The size at presentation usually depends on the location of the tumor. Tumors in the distal extremities are often small when discovered, whereas tumors in the proximal extremities and retroperitoneum can become quite large before they are apparent. Soft tissue sarcomas grow in a centrifugal fashion and compress surrounding normal structures, but rarely does impingement on bone or neurovascular bundles produce pain, edema, and swelling. Infrequently, patients may initially exhibit obstructive gastrointestinal symptoms or neurologic symptoms related to compression of the lumbar or pelvic nerves.

The differential diagnosis of a soft tissue mass includes benign lesions, including lipomas, lymphangiomas, leiomyomas, and neuromas. Besides sarcomas, other malignant lesions, such as primary or metastatic carcinoma, melanoma, or lymphoma, must also be considered. Small lesions that have not changed for several years may just be closely observed. However, biopsy should be considered in patients with all other types of tumors to establish a definitive diagnosis.

Diagnostic Imaging

The doctor performs a physical exam and may use the following procedures and tests to diagnose soft tissue sarcoma:

• X-rays create images of areas inside the body on film. Pretreatment radiologic imaging is critical for defining the local extent of a tumor, staging the disease, guiding biopsies, and aiding in diagnosis. Imaging studies are also crucial in monitoring tumor changes after treatment, especially after preoperative chemotherapy or radiation therapy, and in detecting recurrences after surgical resection. Each imaging modality, however, has a particular place in patients with soft tissue sarcomas. Although radiography is useful for providing information on primary bone tumors, it is not useful for evaluating soft tissue tumors of the extremities. Nonetheless, chest radiography should be performed in patients with primary sarcoma to look for lung metastases.

• Computed tomography (CT) can determine whether a soft tissue tumor has metastasized (spread) to the lung or abdomen. CT scans, also called CAT scans, can also be helpful in determining the size of the tumor and whether the tumor can be accessed through surgery. CT of the chest should be considered for patients with high-grade lesions or tumors larger than 5 cm (T2). Contrast-enhanced CT can assess the extent of the soft tissue tumor burden and the proximity of the tumor to vital structures. CT is also the preferred imaging technique for evaluating retroperitoneal sarcomas. Current techniques can provide detailed information on the abdomen and pelvis and delineate adjacent organs and vascular structures. CT of the abdomen and pelvis should also be done when a myxoid liposarcoma is identified in an extremity, because this subtype of soft tissue sarcoma often metastasizes to the abdomen.

• Magnetic resonance imaging (MRI) scans can aid in diagnosis, particularly in helping to distinguish soft tissue sarcomas from benign tumors, as well as showing the extent of the tumor. MRIs are also used to monitor the patient after treatment to see if the tumor has recurred. MRI is the preferred imaging modality for extremity sarcomas. It can accurately delineate muscle groups and distinguish among bone, vascular structures, and tumor. Sagittal and coronal views can show the anatomic compartments in three dimensions. Special techniques, including magnetic resonance angiography, can be performed if adjacent vascular structures must also be delineated. Before the start of chemotherapy, contrast-enhanced T1-weighted MRI can be used to determine the existence and extent of intratumoral necrosis. MRI is also valuable for identifying tumor recurrence after surgery; a baseline image is usually obtained three months after surgery.

• A biopsy is the removal of cells or tissue for examination by a pathologist. The pathologist studies tissue samples under a microscope or performs other tests on the cells or tissue. A biopsy is the only sure way to tell whether a person has cancer.

Biopsy Techniques

Fine-needle Aspiration Biopsy

Fine-needle aspiration biopsy is an acceptable method for the diagnosis of most soft tissue sarcomas, particularly when it is performed in conjunction with clinical and imaging studies. Fine-needle aspiration biopsy is the procedure of choice to confirm or rule out a metastatic focus or local recurrence. If tumor grading is essential for treatment planning, fine-needle aspiration biopsy has limitations. However, an interventional radiologist may need to perform the biopsy of deeper tumors under sonographic or CT guidance. The diagnostic accuracy of fine-needle aspiration biopsy-based findings in patients with primary tumors ranges from 60% to 96%. In general, the amount of material obtained by fine-needle aspiration biopsy is small, and the diagnostic accuracy clearly depends on the experience and skill of the cytopathologist.

Core-needle Biopsy

Core-needle biopsy is a safe, accurate, and economical procedure for diagnosing soft tissue sarcomas. In addition, enough tissue is usually obtained for use in several diagnostic tests, such as electron microscopy, cytogenetic analysis, and flow cytometry. Complications occur in less than 1% of patients who undergo core needle biopsy. The use of CT or sonography to guide a core-needle biopsy can increase the yield of tumor tissue by more accurately pinpointing the location of the tumor. Obviously, it is particularly important to precisely locate the needle in the tumor mass to avoid sampling necrotic or cystic areas of the tumor that are of no diagnostic value. The diagnostic accuracy of core-needle biopsy-based findings is reported to be 93%.

Incisional Biopsy

Open biopsy is a reliable diagnostic method that obtains adequate tissue. However, incisional biopsies are usually performed only when fine-needle aspiration biopsy or core-needle biopsy specimens yield nondiagnostic findings. An open biopsy ideally should be performed in a designated treatment center by the same surgeon who will perform the definitive surgery. The biopsy incision should be oriented longitudinally along the extremity to allow a subsequent wide local excision that encompasses the biopsy site, scar, and tumor en bloc. A poorly oriented biopsy incision can result in an excessively large surgical defect from a wide local excision, which in turn necessitates a larger postoperative radiation therapy field to encompass all tissue at risk. Adequate hemostasis must also be achieved at the time of biopsy to prevent the dissemination of tumor cells resulting from the formation of hematomas in adjacent tissue planes.

Excisional Biopsy

An excisional biopsy of easily accessible (superficial) extremity or truncal lesions smaller than 3 cm can often be performed. However, the benefits of excisional biopsies rarely exceed those of other biopsy techniques, and these procedures may also cause postoperative complications that could ultimately delay definitive therapy.

• Specialized testing of the tumor cells for chromosomal alterations may also be conducted to aid in diagnosis. With the advent of molecular diagnosis, considerable progress has been made in both accuracy of diagnosis and in understanding of the potential genetic aetiological factors. Many sarcomas carry a characteristic molecular imprint which allows their precise definition. The description of fusion transcripts seen with synovial sarcoma allows the diagnosis of such tumors, characteristically thought of as adolescent and adult tumors, to be identified in all age groups, and this genetic signature allows the identification of synovial cell sarcoma in sites not previously considered commonplace, such as the heart, brain and diaphragm. It is clear that these lesions have nothing to do with the synovium and would be better redefined, but that would seem unlikely. Evaluation of tissue micro-arrays has allowed the distinction to be made between tumors whose behavior is difficult to characterize. Progressively, the unique characterization of genetic fusion products has been described and multiple other potential tumor suppressive tumor oncogenes have been examined, for example Rb. However, the ability of these individual surface oncogenes, or tumor suppressor genes, to be independent factors in outcome has not yet been proven. It is equally true that behaviour of individual histologic subtypes is clearly determined by the subtypes, i.e. the widely differing behavior of liposarcoma with well-differentiated liposarcoma only rarely, if ever, having metastatic disease, whereas the more pleomorphic sarcomas have a high rate of metastatic dissemination.

Treatment for soft tissue sarcomas is determined mainly by the stage of the disease. The stage depends on the size of the tumor, the grade, and whether the cancer has spread to the lymph nodes or other parts of the body.

Treatment options for soft tissue sarcomas include surgery, radiation therapy, and chemotherapy. Accurate preoperative histologic diagnosis is of critical importance in choosing the appropriate primary treatment strategy for patients with soft tissue sarcomas. An intact primary tumor following biopsy affords the best opportunity for the treatment planning team to evaluate the tumor’s proximity to vital structures and for the surgeon to achieve a surgical resection with negative histologic margins. In addition, the tumor can serve as a biologic marker of response in patients who are to be enrolled in preoperative treatment protocols.

The overall five-year survival rate in patients with soft tissue sarcomas of all stages remains only 50% to 60%. Most patients die of metastatic disease, which becomes evident within two to three years of the initial diagnosis in 80% of cases. However, several subsets of patients have benefited from multimodality treatment approaches. For example, a multidisciplinary approach is taken in patients with soft tissue sarcomas of the extremities; it includes a margin-negative resection plus radiation therapy to the tumor bed and has resulted in local control rates up to and exceeding 90%. Nonetheless, despite improvements in local control rates, metastasis and death remain significant problems in patients with high-risk soft tissue sarcomas. Patients considered at high risk of recurrence and death include those presenting with metastatic disease, localized sarcomas at sites other than the extremities, or sarcomas larger than 5 cm of an intermediate or high histologic grade (T2). Patients with abdominal sarcomas continue to show particularly high rates of recurrence and poor overall survival.

Surgery is the usual treatment for soft tissue sarcomas. For surgery to be effective, the surgeon must remove the entire tumor with negative margins. Some patients need reconstructive surgery. The type of surgical resection is determined by several factors, including tumor location, tumor size, the depth of invasion, the involvement of nearby structures, the need for skin grafting or autogenous tissue reconstruction, and the patient’s performance status. Local therapy consisting of surgery, either alone or in combination with radiation therapy when wide pathologic margins are limited by anatomic constraints, is the approach taken in patients with small (less than 5 cm) primary tumors with no evidence of distant metastatic disease. However, amputation remains the treatment of choice for the estimated 5% of patients whose tumor cannot be grossly resected with a limb-sparing procedure that preserves function. Wide local excision is the primary treatment strategy for extremity sarcomas, with the goal to resect the tumor with a 2-cm margin of surrounding normal soft tissue. The biopsy site or tract (if applicable) should also be included en bloc with the resected specimen. Soft tissue sarcomas are generally surrounded by a zone of compressed reactive tissue that forms a pseudocapsule, which may mistakenly be used by inexperienced surgeons to guide resection (enucleation). Microscopic extensions of tumor beyond the pseudocapsule must always be considered when planning surgery and radiation therapy. Patients with microscopically positive surgical margins are at increased risk of local recurrence. Indeed, margin status after surgical resection is an independent prognostic factor for local recurrence. However, negative margins cannot be attained in some anatomic areas because of the tumor’s proximity to vital structures. In addition, because neither a positive surgical margin nor local recurrence has been shown to clearly adversely affect overall survival, this should be taken into consideration if achieving clear surgical margins would require amputation or substantial functional compromise of an extremity.

• Radiation therapy, also called radiotherapy, involves the use of high-energy rays to kill tumorous cells. This therapy may be used before surgery to shrink the tumor, after surgery to kill any cancer cells that may remain in the body, or both before and after surgery. Radiation may come from a machine outside the body (external radiation therapy). It can also come from radioactive materials placed directly into or near the area where the cancer cells are found (internal radiation therapy or radiation implant).

• Chemotherapy may be used before or after surgery, and with or without radiation therapy. The effectiveness of current anticancer drugs depends on the type of sarcoma. Some sarcomas are very responsive to chemotherapy, while others do not respond to current anticancer drugs. Some sarcomas with specific chromosomal alterations can be treated with therapies targeted to the alteration. For example, imatinib mesylate (Gleevec) is a targeted therapy used to treat GIST that has metastasized.

New types of treatment are being tested in clinical trials. These include the following:

High-dose chemotherapy with stem cell transplant

High-dose chemotherapy with stem cell transplant is a method of giving high doses of chemotherapy and replacing blood -forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These reinfused stem cells grow into (and restore) the body's blood cells.

Targeted drug therapy

Targeted therapy is a type of treatment that uses drugs or other substances to find and attack specific cancer cells without harming normal cells. Imatinib (Gleevec) is a new type of targeted therapy called a tyrosine kinase inhibitor. It finds and blocks an abnormal protein on cancer cells that causes them to divide and grow. Targeted therapy may be used for gastrointestinal stromal tumors that cannot be removed by surgery or that have spread to other parts of the body.

In the I-II stages 5-year survival achieves 70-80%.

In the advanced cases (III-IV stages) 5-year survival is less than 30%.

The more common reasons of the death are the distant metastases (to the lungs, bones, liver & brain).

Lecture 13

Skin cancer

Precancerous skin diseases

Non-cancerous skin growths – is a big and various in its origin group of tumors. There are two groups of precancerous conditions:

1) Optional precancerous growths, which are rarely developed into the malignant growths granted timely treatment.

2) Obligate precancerous growths. Which are always developed into the malignant growth.

The facultative precancerous growths include: skin horn, keratosis, senile skin atrophy, atheroma, deep skin mycosis, keratoachanthoma, papilloma, red flat herpes.

Skin horn is cone-shaped new growth, which stands out of the skin level, it has thick brown corneous surface and soft tissue. Most often it is localized on the face skin, eyelids, auricles, hairy part of the head. Women are more susceptible to it. About 10-12 % of patients had skin horns developed into the malignant growth. The treatment is surgical operation.

Keratosis is characterized by dystrophic skin changes, which are presented by the spots of keratinized layers of different thickness, grayish-yellowish color. Mostly localized on the face skin, hairless part of head, body skin. The treatment is surgical operation – excision and electrocoagulation.

Senile skin atrophy – it is shown by the thinning of the skin. In this case the skin is withered, wrinkled, it peels off, it is possible to see the enlarged small blood vessels. (telangiectasis ). The treatment is surgical operation.

Keratoachanthoma – non-malignant growth of the epidermis, which is hardly distinguished from the skin cancer not only clinically but also histologically. Therefore it has many synonyms: plural self-cured skin carcinoma, sebaceous mollusk etc. Mostly elderly people have it, it is single, mainly it is localized on the face skin, on the hands. Clinically it is thick, quickly growing nodule having hemispherical surface and a cavity in the center, covered by x-disease-shaped coat. It has a tendency to self-evolution. The treatment is surgical excision, electrocoagulation, cryodestruction.

The obligate growths include the pigmentary parchment-skin, Bouen tumor, Cair disease.

Pigmentary parchment-skin – was first described by Caposhy M. in 1870 and is considered as rare hereditary diseases, originated from the DNA inability to restore the damage caused by the ultra-violet rays. The disease is manifested by the heightened sensibility to the sun rays from childhood. In the beginning especially on the open body parts disseminated skin pigmentation as plural spots and freckles appears. The skin swells, gets red. Erythema is changed to disseminated rounded pigment spots. Further skin becomes withered, here and there it is atrophic, easily damaged. Enlarged skin blood vessels are seen in these sections – telangiectasis. Gradually ulcers and warty overgrowths appear on the skin. Under existing conditions even teenagers may have basal- and planocellular cancer and also melanoma. In case of pigmentary parchment-skin there is a great likelihood of primary-plural synchronous and metachronous tumors development.

If cancer appears on the background of the pigmentary parchment-skin, it develops slowly and is very sensitive to radiotherapy. As preventive measures against malignancy of the pigmentary parchment-skin it is possible to use sunscreen ointments, to cover the open parts of body with the sunscreen creams.

Bouen tumor – (Bouen diskeratosis) shows itself as various spots with characteristic polycyclic contours. Their surface is covered with hardly removed scabs. When the scabs are removed it is possible to see a smooth surface, sometimes moist papillary surface ( eczematous type). Most often the body skin is affected. The disease is always ended up by malignant transformation.

The treatment is excision in the limits of the healthy skin and in case of the malignization the medical tactics of the skin cancer is used.

Skin cancer (Cancroid)

In the structure of oncological diseases the skin cancer covers 10-15% of all oncological growths.

Epidemiology

The sickness rate in case of the skin cancer is characterized by great cycling. The biggest number of the diseases is observed in the countries with high isolation level. For example in Bulgaria the sickness rate is 36 for 100.000 of inhabitants, whereas in England it is 1.9, and in Ukraine – 35-38 cases for 100.000 inhabitants. It is observed that countrymen are more likely to have the skin cancer than the city dwellers.

Etiology

The factors which cause the skin cancer development are: high isolation, long-term contact with chemical carcinogens – the products of oil refining, coal, shale oils, arsenic combinations, ionizing radiation, constant skin injuries ( mechanical injuries, burns).

Patamorphology of the skin cancer

The skin cancer is developed from the basal cells of the multi-layer flat skin epithelium. According to the histological structure it is possible to identify two forms of the skin cancer: basal-cells (basalioma) and planocellular ( keratinized and non-keratinized). Basalioma is observed in 60% of skin cancer cases, planocellular carcinoma is observed in 30%. Non- non-keratinized form of the planocellular cancer is lowly differentiated tumor and is characterized by quick infiltrative growth.

International classification according to the TNM system:

T- primary tumor

TX-there is no enough evidence for the primary tumor

T0- the primary tumor is not identified

Tis- Carsinoma in situ

T1-the tumor is 2 cm in the maximum measurement

T2- the tumor is more than 2 cm, but less than 5 cm in the maximum measurement

T3- the tumor is more than 5 cm in the maximum measurement

T4- the tumor grows into the lower organs ( cartilages, muscles, bones).

In the case of synchronic primary-plural cancer, when there are several primary tumors it is necessary to indicate their number in parentheses T2 ( 5). The T value is evaluated by the biggest tumor.

N- the regional lymph nodes

Nх- there is no enough evidence for the evaluation of the regional lymph nodes

N0- there is no evidence of the regional lymph nodes affection

N1- the regional lymph nodes are affected

M- distant metastasis

MX- there is not enough evidence to identify distant metastasis

M0- distant metastasis are not identified

M1- there are distant metastasis

|Stage 0 |Tis |N0 |M0 |

|Stage I |T1 |N0 |M0 |

|Stage II |T2 |N0 |M0 |

| |T3 |N0 |M0 |

|Stage III |T4 |N0 |M0 |

| |Any T |N1 |M0 |

|Stage IV |Any T |Any N |M1 |

Clinical description

The clinical picture of cancer depends on the histological structure, on the differentiation stage and on the tumor localization.

The planocellular cancer is the most often observed with the elderly people, mainly situated on the face skin, auricles, upper and lower extremities, external genitals. Clinically it is possible to identify three forms of the skin cancer: surface, infiltrative or deep-penetrative and papillary.

The surface cancer is characterized by the white dense nodules with yellow or white-grey tint, which can be localized at the skin level or higher. As developed the central part becomes wet, erosions are created, the surface becomes rough, pink colored, sometimes it is bleeding, it is covered with crusts, in periphery a thick roller-shaped growth can be formed. The lower part of skin gets red, the evidence of the inflammatory process appears. The characteristic feature of the tumor development is the absence of pain even in case of the large dimension.

The infiltrative form is initially characterized by the appearance of moving, hard, uneven nodules, which are covered by the unchanged epidermis. As developed the nodules are transformed into the sores, infiltrate the subjacent tissues, the borders get firm, become roller-shaped and unmoving when palpated, they early create metastases in the regional lymph nodes. These forms are less successful in prognosis.

The papillary forms of cancer are characterized by the partial growth into the depth of tissue, partial growth upwards to the surface, forming exofitic component, as uneven-like growths, with clear contours. Its surface is covered by shallow sores, which often bleed. The big cancerous sores are characterized by the dense painless metastases in regional lymph nodes. The basal-celled cancer also in many cases appears at an elderly age and is localized mostly on the face skin. Clinically it is characterized by the appearance of the grey-pink dense nodule, which merges with the skin and stands out on its surface. The tumor surface shells off, it is characterized by the ulceration, which deepens with the growth of the tumor. The sore has thick bottom, undermined borders, and it is painless. The tumor develops gradually, affecting more and more areas of the skin. In this case there are no reactive changes and the state of the patients remains satisfactory.

Nodal or exofitic form of the basal-celled cancer grows as the raised on the skin surface nodule on the wide basis. Gradually deep cracks appear between separate parts, where secretions of blood and pus with objectionable odor may accumulate. The basal-celled cancer is not characterized by metastases.

Diagnostics

To diagnose the skin cancer it is important to use examination, palpation, dermatoscopy and it is obligatory to perform cytological analysis of the scrape, smear, incisionary biopsy. To diagnose the metastases in the regional lymph nodes it is common to use the sonography- of the distant metastases, the radiography of the pectoral cavity organs and the ultrasonography of the abdominal cavity. These methods are sufficient to diagnose.

Differential diagnostics:

• Red Lupus

• Tuberculosis

• Syphilitic gumma

• Actinomycosis

• melanoma

• Non-malignant skin growths

Treatment

In case of the flat-celled skin cancer it is possible to use surgery, radiotherapy and medicines. All these methods should be based on the strictly individual factors, considering the tumor localization, clinical form, the disease stage and the histological structure. Beside that the treatment should foresee functional and cosmetic after-effects. Most of the authors believe that in the I-II stages of the disease the radiotherapy is the most effective method ( the most effective is closely-focused radiotherapy, total dose is 30-60 gr.), in case of III-IV stages they use combined method. The surgical method requires - wide ablation of the tumor with the healthy skin area around it ( not less than 2 cm) together with the hypodermic cellular tissue and fascia. In those cases when it is impossible to make a wide ablation ( on the face), the surgical treatment is combined with the radiotherapy or just use the radiotherapy.

In the presence of the enlarged regional lymph nodes, on suspicion of having metastasis, lymphadenectomia is performed at the same time with the excision. In those cases when the big mass of the tumor does not allow to use the above-mentioned methods of treatment, the chemotherapy is applied.

In case of the basal-celled skin cancer the following methods of treatment are used:

1)electroexcision –is applied in case of the tumors less than 1 cm in diameter ( the recovery takes place in 95 % of cases).

2) closely-focused radiotherapy – is applied in case of the face tumors (to prevent the cosmetic defects). The recovery takes place in 90 % of cases. The defect of the method is – depigmentation and the skin atrophy in the area of the radiation treatment.

3) Excision with the primary wound closing. The recovery takes place in 95% of cases.

4) When the cryotherapy of the skin cancer is used, it is necessary to do three-fold freezing of the tumor in the scope of the 0.5-1 cm of the healthy skin until its complete destruction. The healing of the wound takes place under the scab during 3-4 weeks with the formation of the elastic cosmetically nice scar. The relapse is treated by the wide excision.

The prognosis in skin cancer case compared with the other malignant tumors is the most favorable. In case of the regional lymph nodes metastases absence 5-years survival is guaranteed in 75-80 % of cases, and when it is early diagnosed almost 80-100 % of patients completely recover and do not have relapses. 5-years survival with the regional lymph nodes -metastases and growing through the close organs and tissues is only 24%.

Non-malignant and malignant skin tumors of the conjunctive tissue-like origin.

Non-malignant and malignant skin tumors of the conjunctive tissue-like origin are comparatively rare, more often in the young age. They are localized mostly on the body skin and upper or lower extremities. Women have them more often.

Among the non-malignant tumors the most frequent are fibroma ( soft and hard), dermatofibroma, lipoma, angioma, gemangioendotelioma, neurofibroma etc. These tumors have different size, form and consistence, they grow slowly. They may be the source of the malignant tumors development ( sarcomas). The treatment used here is surgical.

Skin sarcomas come to 0.3% of the malignant tumors and are found with the elderly people.

The histological classification of the skin sarcomas made by F.Faitcheva and V. Andreyeva ( 1965):

1.The tumors of formed dense conjunctive fibrous tissue ( fibrosarcoma and dermatosarcoma Darie).

2. The tumors of the fat base ( liposarcoma)

3.The tumors of muscle tissue ( miosarcoma)

4. The tumors of the blood and lymphatic vessels ( angiosarcoma, angioendotelioma, Caposhy sarcoma, lymphangiosarcoma).

5.The tumors of the undifferentiated cells (undifferentiated sarcoma, mixosarcoma).

The clinical picture.

Fibrosarcoma represents the single dense nodule, which is raised above the skin surface. The tumor size amounts to 10 cm and more. The color of the skin is rosy which turns into azure-red. Fibrosarcoma grows slowly and is rarely ulcerates.

Dermatosarcoma Darie – the tumor has flat plaques-like surface with the outstanding nodules. The skin which covers them is normal. It grows slowly and rarely creates metastasis, but it can relapse. The growth of the nodules can be accompanied by change of their color, in which case they get blue-brown tint. Sometimes the nodules become big, uneven and bleed. The tumor is more often localized on the abdominal wall and thorax wall.

Liposarcoma is rarely found. It is clinically characterized by the appearance of the single nodule which is situated in the hypodermic base. Its growing speed depends on the histological form. The differentiated sarcoma grows slowly and undifferentiated sarcoma may grow quickly. It can amount to the great size, and may be characterized by the ulceration.

Angiosarcoma is rarely found. It has rough surface of bluish-reddish color, often creates metastasis, can be characterized by the ulceration and bleeding.

Idiopathic plural haemorrhagic sarcoma ( Kaposhy sarcoma) is called after the author, who first described it in 1972. There are about 35 synonyms –names of this tumor ( pigmentary and teleangiectatic sarcomatosis, plural angioplastic pigmentary sarcoma etc).

Histogenesis of this tumor is not mostly identified, but it is at the center of attention because it belongs to the acquired immunodeficiency syndrome (AIDS).

The disease starts with the appearance of several pink nodules, which are localized mostly in the area of distal, often symmetrical parts of the extremities.

Further new dense plural nodules appear, which merge and begin to occupy more of the extremities surface or body surface, forming compact red-purple flat tumors of the irregular shape. At the same time the significant hypostasis of the lower extremities may occur - elephantiasis. In the case of AIDS the face is more likely affected. Patients complain about itching, pain, bleeding and lymph ( лимфотечение) of the affected areas. The tumor creates metastases. The course of the disease is enduring with the periods of remission. The process has overall character with the spreading to the proximal parts of the extremities and formation of the tumor nodules in the internal organs, but sometimes there are cases of the spontaneous remission. The tumor nodules can bleed. The disease is accompanied with the growing cachexy.

The treatment of the skin sarcoma - is surgical, closely-focused radiotherapy with corticosteroids. In cases of the generalized forms of Kaposhy sarcomas the cytostatic therapy is used – the combination of doxorubicin, vinblastin and bleomicin, and also monochemotherapy with the prospidin. As the biotherapy they use intron A. The timely treatment gives a positive result.

Lecture 14

Melanoma

Melanoma – is the malignant pigmentary tumor. The term “melanoma” ( from the Greek “melanos” – black, dark) was suggested by Carswell in 1838. The synonyms of melanoma: melanoblastoma, novocarcinoma, melanomalignoma.

Epidemiology.

The melanoma constitutes 1-10% of the malignant skin tumors and 0,3-0,9% of all malignant human tumors. According to the official returns of the International anticancer union the sickness rate in case of melanoma is 0,1-6,9 persons for 100.000 population in different countries of the world, and the average annual sickness rate rise of this tumor in the world is about 5% ( in the USA – 4%, in Russia -3,9%) and may be considered one of the highest among all malignant tumors. Most often the melanoma is localized on the skin ( 70-80%), rarely in the eye area ( 5-7%) and it is very rare in the area of other organs (gullet, rectum). In the Minor Asia countries the indigenous people have melanoma 3,5 times rarely than the representatives of other nationalities, who live in those states.

Etiology.

There are exogenous and endogenous factors in the development of the melanoma.

1.The exogenous risk factors. This group is represented by the physical, chemical and biological agents of the environment, which can directly and immediately effect the skin.

• Physical factors: ultra-violet radiation from the sun, ionizing radiation, electromagnetic radiation, fluorescence illumination, nevus traumatism.

• Chemical factors: harmful chemical agents used in the petrochemical, chemical ( in particularly producing nitric acid), producing rubber plants, in the production of vinyl chloride, polyvinyl chloride, plastic, benzol, pesticides.

• Biological factors: the nutrition quality (high level of daily protein and adipose consumption), medical products (exogenous estrogens).

2. Endogenous risk factors. There are two groups:

1) Biological constitution features, which presence raises the risk of the melanoma development: racial and ethnic predisposition, the level of the body pigmentation, hereditary (family) factors, anthropometric indexes, immune failings, endocrine factors, reproductive women’ factors.

2) The second group is represented by the predecessors of the melanoma, that is such pathological skin changes , which can have the probability of the malignant mutation: pigmentary parchment-skin, Dubrei melanosis, nevuses.

Precancerous Dubrei melanosis ( synonyms: melanosis Hatchinson spot, limited precancerous melanosis, senile lentigo) is the pigmentary spot of different size, of irregular oval shape, brown color of various intensity and strongly marked along the edges. It has the rough surface- atrophic here and there, hyperkeratic and papillomatous. Most often it is localized on the face skin, rarely on the body skin, on the neck, hairy part of head, external women’s genitals. Dubrei melanosis significantly less than the following nevuses can be the origin of the melanoma development.

The increased accumulation of the melanoblasts in the various skin layers is called nevus ( from latin naevus – birthmark). The nevuses can be innate and acquired.

Blue nevus, or Yaddason Tiche nevus , also Otta nevus – is sharply bounded round or oval new growth with more or less marked pigmentation, they are rarely found and rarely turn into the melanoma, that is why in practical sense they are not dangerous.

Gigantic pigmentary nevus- innate development anomaly. Clinically it shows itself as skin pigmentation of various size ( from the palm size or bigger on the body skin or extremities). The surface of the gigantic nevus can be warty, covered with deep sores or with intensive hairiness.

In this connection it is common to distinguish pigmentary papillomatous, verrucous and hairy nevus. The color of the nevus can be different – brown, black, grayish. Gigantic pigmentary nevus presents a serious cosmetic defect.

Fibroepithelial nevus – is a round new growth, which raises above the skin, having soft elastic consistence, brown color of different intensity. It is mostly localized on the face rarely –on the body. It is almost never becomes malignant, but patient often address to doctor because of the cosmetic reason.

Verrucous or papilloma-like nevus – growths of various shape, which raise above the skin surface. Their surface is uneven, sometimes hyperkeratical, from light-brown to dark-brown color. Verrucous nevus is most often localized on the body and extremities, papillomatous nevus is localized on the hairy part of the head.

The patient’s reasons to address the doctor are: nevus traumatism or growth, weeping nevus, unpleasant smell, pain, itching, cosmetic defect. That is why any unpleasant sensations in the area of nevus should be regarded by the doctor as the threat of melanoma development regardless of its belonging to the category melanoma -risk nevus.

Pathomorphology of the melanoma.

The tumor develops from the pigment cells melanocitis. It is characterized by the presence of the melanin pigment accumulation, although there are sometimes pigmentless forms. Histologically it is common to distinguish 4 types of the cellular melanoma system: epithelial, spindle-celled, mixed and small-celled. It is hard to consider the melanoma unambiguously among the malignant epithelial tumors or tumors of the conjunctive tissue –like ( соединительный) origin.

Metastases.

The melanoma occupies a special place among the malignant tumors, as capable of quick metastases spreading. Practically there is no organs, where the melanoma could not create metastases. But primarily it creates metastases in the regional lymph nodes. It is important to note that in clinically unchanged lymph nodes of 18-40% of patients metastases are histologically found.

(Gematogenously) Through the blood the melanoma creates metastases practically in all organs and tissues. With all this going on, the metastases in the inner organs can appear earlier than in the lymph nodes. Very often gematogenous metastases in the skin can develop.

International classification according to the TNM system:

T- primary tumor

Tis- melanoma in situ

T1-the tumor is less than 1mm thick; a) without ulceration and the invasion level is II/III b)with ulceration or invasion level is IV/V.

T2- the tumor is 1,01-2.0 mm thick, a) without ulceration b)with ulceration

T3- the tumor is 2,01-4,0 mm thick; a) without ulceration b)with ulceration

T4- the tumor is more than 4 mm thick a) without ulceration b)with ulceration

N- regional lymph nodes

N1- metastases in 1 gland a)micrometastases 1; b)macrometastases 2

N2-metastases in 2-3 lymph nodes a) micrometastases1; b)macrometastases2 c)transitional metastases/satellites without metastatic lymph nodes

N3-4 and more metastatic lymph nodes or the conglomeration of lymph nodes, or transitional metastases/satellites with metastatic lymph nodes

M-distant metastases

1a- there are distant metastasis on the skin, hypodermic or in the lymph nodes.

M1b – metastases in the lungs.

M1c – other visceral or any distant metastases.

1-micrometastases are diagnosed after the observation or selective lymphodenectomia.

2.- macrometastases - are clinically found metastases in the lymph nodes, confirmed by the therapeutical lymphodenectomia or extracapsular spreading of metastases in the lymph nodes.

Classification according to stages:

| |Clinical stages |Morphological stages |

| |TNM |pTNM |

|0 |Tis |N0 |M0 |Tis |N0 |M0 |

|IA |T1a |N0 |M0 |T1a |N0 |M0 |

|IB |T1b |N0 |M0 |T1b |N0 |M0 |

| |T2a |N0 |M0 |T2a |N0 |M0 |

|IIA |T2b |N0 |M0 |T2b |N0 |M0 |

| |T3a |N0 |M0 |T3a |N0 |M0 |

|IIB |T3b |N0 |M0 |T3b |N0 |M0 |

| |T4a |N0 |M0 |T4a |N0 |M0 |

|IIC |T4b |N0 |M0 |T4b |N0 |M0 |

|III |Any T |N1 |M0 | | | |

| | |N2 |M0 | | | |

| | |N3 |M0 | | | |

|IIIA | | | |T1-4a |N1a |M0 |

| | | | |T1-4a |N2a |M0 |

| | | | | | | |

|IIIB | | | |T1-4b |N1a |M0 |

| | | | |T1-4b |N2a |M0 |

| | | | |T1-4a |N1b |M0 |

| | | | |T1-4a |N2b |M0 |

| | | | |T1-4a/b |N2c |M0 |

|IIIC | | | |T1-4b |N1b |M0 |

| | | | |T1-4b |N2b |M0 |

| | | | |Any T |N3 |M0 |

|IV |Any T |Any N |Any M 1 |Any T |Any N |Any M1 |

Clinical picture.

Women are more likely to have the melanoma. 35-45 % of men have this disease. Melanoma is mostly observed at the age of 30-60, its clinical picture can be various, which can often present difficulties in diagnosing correctly.

The main signs of the nevuses malignisation are:

• Disappearing of the skin pattern on the nevus surface;

• appearance of the shiny, glossy nevus surface;

• appearance of the asymmetry or contours irregularity (scalloped) contours of nevus, that is changes of its shape;

• Horizontal nevus growth;

• Appearance of the subjective heat sensation, itching or pain in the nevus area;

• Appearance of the single nodules ( satellites) around nevus;

• Appearance single nodules on the surface of the nevus without its visual growth

• Peeling of the nevus surface with the formation of the withered “scabs”;

• Absence of hair or shedding of the hair on the nevus surface

• Partial (irregular) or complete color change of nevus –melanoma ( melanoma) – appearance of the areas of so called bound depigmentation;

• Vertical growth of nevus- melanoma above the surrounding areas.

• The consistence change of the nevus-melanoma, which is defined with palpation, that is its softening;

• Ulceration of the epidermis above the nevus-melanoma;

• Inflammation in the area of the nevus-melanoma and surrounding tissues;

• Weeping of the nevus-melanoma surface

• Bleeding of the nevus-melanoma.

There are several clinical-anatomical forms of the melanoma:

1.Superficial melanoma with horizontal growth is 70% of all melanomas. Clinically it is contoured formation, which rises above the skin surface, of brown color. Atypical cells are localized in the upper layers of derma, spreading in lateral direction. The prognosis is favorable as a rule.

2. Nodule-like ( nodous, nodular) form is found in 15% of cases. The tumor is shaped like the flat nodule, rising above the skin suface, sometimes it is shaped like polypus on the stem, of blue color, without any particular localization, and mostly observed at the elderly age. The tumor cells spread vertically with quick derma invasion. The prognosis is unfavorable.

3.Acrolentigo-like and mucous melanoma ( 10% of all melanomas). The tumor has irregular contours, black, can be pigmentless. It grows slowly in radial direction, usually in the upper layers of derma ( on the palms, feet). The prognosis depends on the degree of the infiltrative tumor growth.

4. Malignant lentigo (melanoma-like freckles) – the rarest form. It develops at the age of 70. It looks like the spot-like nodules from yellow-brown to almost black color, 1,5-3mm in diameter, and are formed in the smooth freckles. The tumor grows slowly, in radial direction in the upper layers of derma. The prognosis is favorable.

The diagnostics of melanoma is difficult because of the many forms of its clinical picture, but the main diagnostics method is clinical one: studying anamnesis, previous skin changes, external tumor shape, the state of the lymph nodes system. Besides that it is common to perform dermatoscopy, echography, tumor thermography and cytological analysis of the smears – the tumor prints, a sentinel node biopsy. Other kinds of biopsy are prohibited. To exclude the presence of metastasis in the glands it is common to do the ultrasonic examination and a sentinel node biopsy of the lymph nodes. The diagnostic puncture of the pigmentary tumor should be as much as possible approximated to the following medical treatment (radiation treatment, surgery).The patient should be completely prepared to the adequate surgery with anesthesia.

Another valuable additional examination is radioisotope scanning with the help of radio-active 32 P. The criteria of malignant mutation for melanoma is threefold increasing ( 300%) of the phosphorus accumulation over the tumor during 72 hours. This method allows to diagnose lymphogenous and gematogenous metastases of the tumor. Also rontgenologic and sonographic examination is performed, to diagnose regional and distant metastases. Also as a way to diagnose they use total cutting excisionary biopsy of the primary tumor.

Differential diagnostics:

• Youth melanoma ( Spits nevus)

• Blue nevus

• Galo-nevus

• Displastic nevuses

• Cavernous thrombotic gemangioma

• Non-malignant skin tumors

• Malignant skin tumors

• underungual, and underepidermal haematoma

• onihomikosis

• extrasexual chancre

• metastases of the other histogenesis tumors into the skin

The treatment of the skin melanoma is mostly surgical. The surgical treatment can be a part of the combined or complex treatment. The main requirements to the surgical treatment:

1. The incision of the skin should be performed within the distance of 3-5 cm from the tumor, in this case it is necessary to step back in the direction of the regional lympho-outflow.

2. It is necessary to ablate in one block the skin, hypodermic cellular tissue and fascia.

3. The surgery should be necessarily performed with the general anesthesia.

4. When there is a suspicion of regional lymph nodes ( jugular, groin, axillary ) having metastases the regional lymphadenectomy should be performed at the same time. The biopsy of the boundary lymph nodes can give enough information about the state of the regional lymph nodes.

5. In most cases when the wound is being sewed up the plastic surgery methods should be applied on the skin.

6. Melanoma in situ ( atypical melanocitar hyperplasia, noninvasive melanoma – I level according to Clark) minimal excision is allowed in principle, on conditions that the borders of resection were free from the tumor when the preparation was examined histologically. In practice the standard excision is less than 1 cm from the visible border of the tumor.

Stage I

Stage IA pT1aN0M0.

The standard treatment in case of IA and IB stages - is wide excision of the tumor at the distance of 2 cm from the tumor borders.

Stage II

Stage IIA pT2b – 3a N0M0, IIB pT3b- 4aN0M0, IIC pT4aN0M0.

The standard excision is at the distance of 3 cm from the tumor borders.

Besides the tumor excision it is possible to perform immunotherapy using interferon a-2b 3 ml ME/m2 of hypodermic injection 3 times per week during 3 years or until the relapse and melanoma metastases.

Stage III

Stages IIIA pT 1-4a N1-2a, Mo, IIIB pT1-4b N1a-2c M0, IIIC pT1-4b N1b, 2b, 3 M0

The medical standard is wide excision of the primary tumor within 3 cm and more combined with the regional lymphodenectomia. In case of need there can be plastic replacement of the skin defect. Chemotherapy ( chemoimmunotherapy), immunotherapy ( interferon a-2b,БЦЖ), polychemotherapy should be performed in usual or modified ( hyperthermia, hyperglycemia etc) conditions. As polychemotherapy dacarbasin is used combined with the medications of platinum ( cisplatin), alkaloids of periwinkle ( vinblastin), the medications of urea nitromesil group (lomustin). The effectiveness of polychemotherapy in this combination is 30-40%, whereas in case of monochemotherapy with dacarbasin it is 15-25%.

Stage IV Any pT, any N, M1.

In spite of the little sensitiveness of disseminated melanoma to the chemotherapy, the standard of this tumor treatment is systemic chemotherapy. The objective reaction to dacarbasin ( DTIC) and the derivatives of nitrosourea- carmustin ( BCNU), lomustin (CCNU) do not exceed 20-25%. Most patients are observed to have remissions from 3 to 6 months, although in some cases there are more prolonged remissions. Along with monotherapy it is possible to apply multi-component schemes including chemotherapeutic medicines, such as vinkaalkaloids, the derivatives of platinum and taxans. The surgical treatment of IV stage melanoma can be performed in the presence of the single metastases in the lungs, gastrointestinal tract, bones or brain. Palliative resections are done, which in some cases are very effective and significantly prolong life. For the cytoreductive purpose palliative lymphadenectomy can be performed. Although the melanoma is rather radioresistant tumor, palliative radiotherapy can relieve the patients state. Retrospective researches testify that with the patients with plural metastases in the brain, the skeleton bones and the spinal cord compression it is possible to achieve the significant reduction of the symptoms and the decrease of the tumor size by means of radiotherapy. It is not established however what function procedure is the most effective in case of the radiotherapy applied to the bones and spinal cord metastases. In addition to melanoma treatment main schemes it is common to use antiestrogens. ( tamoksifen).

Local relapses.

Not long ago among the local relapses were all repeatedly appearing tumors, localized in the postoperative scar or in the skin area, as well as in the skin or hypodermic cellular tissue at the distance of 5 cm from the scar or skin area ( лоскут). At the present time the local relapse is the repeated tumor within 2 cm from the postoperative scar. The standard treatment of the local relapses is an excision within the limits of the healthy tissues ( 1-3cm, depending on the anatomic localization). The alternative method of the local relapses treatment of the melanoma on the extremities is regional hyperthermic perfusion.

The frequency of the complete remissions when using tumor-necrotic factors and melfalan attains 90%. In case of the absence of the complete regress the residual changes should be excised. Since the regional relapses in more than the half patients’ cases are accompanied transit metastases, the performance of the regional chemotherapy becomes especially urgent. The influence of the regional perfusion on the patients survival is not proved.

The prognosis.

The prognosis in case of the skin melanoma depends on many factors, but mainly on the progress stage, localization, size, the growth form of the tumor, on the patients age and sex, on the character and adequacy of the chosen treatment method. In case of the localized process 5-years survival is possible in 75-86 %, 10-years – 47%, in case of the regional metastases - 33-52% and 13% accordingly, in case of the distant metastasis 5-years survival does not exceeds 5-12%.

Lecture 15

Cervical cancer

Epidemiology

Cervical cancer is a malignancy of the cervix. Worldwide, it is the second-most common cancer of women. It may present with vaginal bleeding but symptoms may be absent until the cancer is in its advanced stages, which has made cervical cancer the focus of intense screening efforts utilizing the Pap smear. Most scientific studies have found that human papillomavirus (HPV) infection is responsible for more than 90% of the cases of cervical cancer. According to a survey of 3,076 women 18 to 75 years of age, awareness about human papillomavirus (HPV) infection and its link to cervical cancer is relatively low among American women. In 2006 an estimated 10,000 women in the United States will be diagnosed with this type of cancer and nearly 4,000 will die from it.

Worldwide, cervical cancer is the second most common cancer in women (after breast cancer) and is the third leading killer (behind breast and lung cancer). It affects about 16 per 100,000 women per year and causes death in about 9 per 100,000 per year. In the Ukraine, howeever, cervical cancer is the 3th most common cancer of women. About 12,800 women in the Ukraine are diagnosed with cervical cancer and about 4,800 die each year. Among gynecological cancers it ranks behind endometrial cancer and ovarian cancer.

Epidemiologists working in the early 20th century noted that:

1. Cervical cancer was common in female sex workers.

2. It was rare in nuns, except for those who had been sexually active before entering the convent.

3. It was more common in the second wives of men whose first wives had died from cervical cancer.

4. It was rare in Jewish women.

5. In 1935, Syverton and Berry discovered a relationship between HPV and skin cancer in rabbits.

Ethiology

Cervical cancer caused by a sexually transmitted agent. Initial research in the 1950s and 1960s put the blame on smegma (e.g. Heins et al 1958), but it wasn't until the 1970s that human papillomavirus (HPV) was identified. A description by electron microcopy was given earlier in 1949 and HPV-DNA was identified in 1963. It has since been demonstrated that HPV is implicated in all cervical cancers. Specific viral subtypes implicated are HPV 16, 18, 31 and 45. There are 7 common types of HPV: 16, 18, 31, 33, 42, 52 and 58. Types 16 and 18 are the most common cause of the cancer. There are “low-risk” viruses which do not commonly turn into cancer and “high-risk” viruses that are most likely to develop into cervical cancer, although both can. Having several sexual partners is a major risk factor for developing HPV. Although most HPV infections clear up on their own, the infections could increase to major abnormalities or cervical cancer.

Doctors can test samples of cervical cells to determine types of HPV that may be present. In some cases, HPV clears up on its own, and in some, there were no signs until it was too late, and cervical cancer developed.

Risk factors

The following list of risk factors for cervical cancer: human papillomavirus infection, smoking, HIV infection, chlamydia infection, dietary factors, oral contraceptives, multiple pregnancies, use of the hormonal drug diethylstilbestrol (DES) and a family history of cervical cancer.

The presence of strains 16, 18 and 31 of human papillomavirus (HPV) is the prime risk factor for cervical cancer. The presence of HPV is a necessary condition for the development of cervical cancer. A virus cancer link with HPV has been found to trigger alterations in the cells of the cervix, leading to the development of cervical intraepithelial neoplasia and cancer. HPV subtypes 16 and 18 introduce two genes called E6 and E7 which code for proteins that inhibit p53 and Rb, which are two important tumor suppressor genes in humans. The p53 gene product is involved in regulation of apoptosis (cell suicide), and Rb is responsible for halting the cell cycle at the G1-phase. When Rb function is impaired, the cell is allowed to progress to S-phase and complete mitosis, resulting in proliferation and hence neoplastic transformation.

Genital warts are caused by different HPV types, and are not related to cervical cancer. The medically accepted paradigm, that a patient must have been infected with HPV to develop cervical cancer, and is hence viewed as a sexually transmitted disease. Not all women infected with HPV also develop cervical cancer. Use of condoms will not always prevent transmission. Likewise, HPV can be transmitted by skin-to-skin-contact with infected areas. HPV is thought to grow preferentially in the epithelium of the glans penis, and scrupulous washing and cleaning of this area may be preventative. The position on circumcision is controversial: some researchers argue that routine neonatal circumcision is an acceptable way of preventing various diseases (which include cervical carcinoma); others maintain that the benefits do not outweigh the risks. However, there has not been any definitive evidence to support this claim.

Symptoms

The early stages of cervical cancer may be completely asymptomatic. Vaginal bleeding, contact bleeding or (rarely) a vaginal mass may indicate the presence of malignancy. Also, moderate pain during sexual intercourse and vaginal discharge are symptoms of cervical cancer. In advanced disease, metastases may be present in the abdomen, lungs or elsewhere. Symptoms of advanced cervical cancer may include: Loss of appetite, Weight loss, Fatigue, Pelvic pain, Back pain, Leg pain, Single swollen leg, Heavy bleeding from the vagina, Leaking of urine or feces from the vagina, and Bone fractures

The possibility to identify premalignant changes on a cervical smear has made screening the major cause for referral of women with possible cervical neoplasia. In many countries, women are advised to have a regular Pap smear to check for premalignant changes.

Recommendations for how often a Pap smear should be done vary from once a year to once every five years. If cervical cancer is detected early, it can be treated without impairing fertility. Consistently abnormal smears may be a reason for further diagnosis despite complete absence of symptoms.

Diagnosis

Diagnosis is made by doing a biopsy of the cervix, which often involves colposcopy, or a magnified visual inspection of the cervix aided by using an acetic acid (e.g. vinegar) solution to highlight abnormal cells on the surface of the cervix (the portio). A Pap smear is insufficient for the diagnosis. Many researchers recommend that since more than 99% of invasive cervical cancers worldwide contain human papillomavirus, HPV testing should be carried out together with routine cervical screening (Walboomers et al, 1999). However, given the prevalence of HPV (around 80% infection history among the sexually active population) others suggest that routine HPV testing would cause undue alarm to carriers.

Further diagnostic procedures are loop electrical excision procedure (LEEP) and conisation, in which the inner lining of the cervix is removed to be examined pathologically. These are carried out if the biopsy confirms severe dysplasia.

Types of malignant cervical tumors include the following:

■ M8070/3: squamous cell carcinoma (about 80-85%)

■ M8140/3: adenocarcinoma

■ M8560/3: adenosquamous carcinomas

■ M8041/3: small cell carcinoma

■ M8246/3: neuroendocrine carcinoma

■ M8720/3: melanoma

■ (varied): lymphoma

Staging

Cervical cancer is staged by the FIGO staging system, which is based on clinical examination, rather than surgical findings. It allows only the following diagnostic tests to be used in determining the stage: palpation, inspection, colposcopy, endocervical curettage, hysteroscopy, cystoscopy, proctoscopy, intravenous urography, and X-ray examination of the lungs and skeleton, and cervical conization.

The TNM staging system .

Stage 0 - full-thickness involvement of the epithelium without invasion into the stroma (carcinoma in situ)

■ Stage I - limited to the uterus

■ IA - diagnosed only by microscopy; no visible lesions

■ IA1 - stromal invasion less than 3 mm in depth and 7 mm or less in horizontal spread

■ IA2 - stromal invasion between 3 and 5 mm with horizontal spread of 7 mm or less

Treatment consists of surgery (including local excision) in early stages

■ IB - visible lesion or a microscopic lesion with more than 5 mm of depth or horizontal spread of more than 7 mm

■ IB1 - visible lesion 4 cm or less in greatest dimension

■ IB2 - visible lesion more than 4 cm

■ Stage II - invades beyond uterus

■ IIA - without parametrial invasion

■ IB - visible lesion or a microscopic lesion with more than 5 mm of depth or horizontal spread of more than 7 mm

■ IB1 - visible lesion 4 cm or less in greatest dimension

■ IB2 - visible lesion more than 4 cm

■ Stage II - invades beyond uterus

■ IIA - without parametrial invasion

Treatment consists of surgery and radiotherapy in advanced stages of the disease

■ IIB - with parametrial invasion

■ Stage III - extends to pelvic wall or lower ⅓ of the vagina

■ IIIA - involves lower ⅓ of vagina

■ IIIB - extends to pelvic wall and/or causes hydronephrosis or non-functioning kidney

■ IVA - invades mucosa of bladder or rectum and/or extends beyond true pelvis

■ IVB - distant metastasis

Treatment consists of chemotherapy and radiotherapy

Note that the FIGO stage does not incorporate lymph node involvement in contrast to the TNM staging for most other cancers.

For cases treated surgically, information obtained from the pathologist can be used in assigning a separate pathologic stage but is not to replace the original clinical stage.

For premalignant dysplastic changes, the CIN (cervical intraepithelial neoplasia) grading is used.

Treatment

Treatment consists of surgery (including local excision) in early stages and chemotherapy and radiotherapy in advanced stages of the disease. An effective vaccine, the HPV vaccine, for the two most common strains of HPV has recently been licenced.

Microinvasive cancer (stage IA) is usually treated by hysterectomy (removal of the whole uterus including part of the vagina). For stage IA2, the Lymph nodes are removed as well. An alternative for patients who desire to maintain fertility is a local surgical procedure such as a LEEP or cone biopsy.

If a cone biopsy was not able to produce clear margins, there is one possible option left for those with early stage cervical cancer who would like to preserve their fertility while treating their cervical cancer: a trachelectomy. For those in stage I cervical cancer, which has not spread, this is a viable treatment option. It allows for the preservation of the ovaries and uterus while surgically removing the cervical cancer. This treatment option is not yet well known amongst doctors and is not yet considered a standard of care. Furthermore, few doctors are trained in this fertility sparing surgical option. Even the most experienced surgeon won't be able to promise that this can be performed beforehand, as the extent of the spread of cervical cancer is unknown until surgical microscopic examination is completed. As a result, there is always the possibility for the need to convert to a hysterectomy if the surgeon is not able to microscopically confirm clear margins of cervical tissue once the patient is under general anesthesia in the operating room. This can only be done during the same operation if the patient has given consent for a possible hysterectomy prior to the operation.

Due to the fact of the possible risk of cancer spread to the lymph nodes in stage 1b cancers and some stage 1a cancers, the surgeon may also need to remove some lymph nodes from around the womb. Once all the checks have been done and if all is well, the cervix will be stitched closed with a cerclage. This will allow for menstruation and fertilization but not dilation for a vaginal delivery, therefore requiring any future births are delivered by cesarean section. A radical trachelectomy is a smaller operation than hysterectomy, but more importantly allows for the preservation of fertility. This operation can also be performed vaginally instead of abdominally, however there are conflicting opinions as to which approach is better. A radical abdominal trachelectomy with lymphadenecectomy usually only requires a 2- to 3-day hospital stay with most women recovering very quickly (approximately 6 weeks).

Complications are generally uncommon, although women who are able to conceive after surgery are prone to preterm labor or possible late miscarriage. It is generally recommended to wait at least one year before attempting to become pregnant after surgery. Recurrence in the residual cervix is a very rare event as long as the cancer has been cleared with the trachelectomy. Even though recurrence is rare, it is generally recommended for patients to practice vigilant prevention and follow up care including pap screenings/colposcopy, with biopies of the remaining lower uterine segment as needed (every 3-4 months for at least 5 years) to monitor for any recurrance in addition to minimizing any new exposures to HPV through safe sex practices until one is actively trying to conceive.

Early stages (IB1 and IIA less than 4 cm) can be treated with radical hysterectomy with removal of the lymph nodes or radiation therapy. Radiation therapy is given as external beam radiotherapy to the pelvis and brachytherapy (internal radiation). For patients treated with surgery who have high risk features found on pathologic examination, radiation therapy with or without chemotherapy is given in order to reduce the risk of relapse.

Larger early stage tumors (IB2 and IIA more than 4 cm) may be treated with radiation therapy and cisplatin-based chemotherapy, hysterectomy (which then usually requires adjuvant radiation therapy), or cisplatin chemotherapy followed by hysterectomy.

Advanced stage tumors (IIB-IVA) are treated with radiation therapy and cisplatin-based chemotherapy.

Vaccine

Merck & Co. has developed a vaccine against four strains of HPV (6,11,16,18), called Gardasil™. It is now on the market after receiving Food and Drug Administration approval on June 8, 2006. Gardasil is targeted at girls and women of age 9 to 26 because the vaccine only works if given before infection occurs; therefore, public health workers are targeting girls before they begin having sex. The use of the vaccine in men to prevent genital warts and interrupt transmission to women is initially considered only a secondary market. The high cost of this vaccine has been a cause for concern. Gardasil has received EU approval.

Glaxosmithkline has developed a vaccine called Cervarix™ which has been shown to be 100% effective in preventing HPV strains 16 and 18 and is 100% effective for more than four years. The two HPV strains (16 and 18) together cause about 70% of cervical cancer cases. Cervarix should be approved by year's end.

Lecture 16

Ovarian cancer

Epidemiology

Ovarian cancer is the fifth leading cause of cancer death in women, the leading cause of death from gynecological malignancy, and the second most commonly diagnosed gynecologic malignancy. It is idiopathic, meaning that the exact cause is usually unknown. The disease is more common in industrialized nations, with the exception of Japan. In the United States, females have a 1.4% to 2.5% (1 out of 40-60 women between 55 and 74 years of age and approximately one quarter of ovarian cancer deaths occur in women between 35 and 54 years of age) lifetime chance of developing ovarian cancer. In the Ukraine – 15,5 causes of 100 000 women.

Older women are at highest risk. More than half of the deaths from ovarian cancer occur in women

The risk for developing ovarian cancer appears to be affected by several factors. The more children a woman has, the lower her risk of ovarian cancer. Early age at first pregnancy, older ages of final pregnancy and the use of low dose hormonal contraception have also been shown to have a protective effect. Ovarian cancer is reduced in women after tubal ligation.

The link to the use of fertility medication, such as Clomiphene citrate, has been controversial. An analysis in 1991 raised the possibility that use of drugs may increase the risk for ovarian cancer. Several cohort studies and case-control studies have been conducted since then without providing conclusive evidence for such a link. It will remain a complex topic to study as the infertile population differs in parity from the "normal" population.

There is good evidence that in some women genetic factors are important. Carriers of certain mutations of the BRCA1 or the BRCA2 gene, more frequent in some populations (e.g. Ashkenazi Jewish women) are at a higher risk of both breast cancer and ovarian cancer, often at an earlier age than the general population.

Patients with a personal history of breast cancer or a family history of breast and/or ovarian cancer, especially if at a young age, may have an elevated risk. A strong family history of uterine cancer, colon cancer, or other gastrointestinal cancers may indicate the presence of a syndrome known as hereditary nonpolyposis colorectal cancer (HNPCC, also known as Lynch II syndrome), which confers a higher risk for developing ovarian cancer. Patients with strong genetic risk for ovarian cancer may consider the use of prophylactic oophorectomy after completion of child-bearing.

A Swedish study, which followed more than 61,000 women for 13 years, has found a significant link between milk consumption and ovarian cancer. According to the BBC, "[Researchers] found that milk had the strongest link with ovarian cancer - those women who drank two or more glasses a day were at double the risk of those who did not consume it at all, or only in small amounts." Recent studies have shown that women in sunnier countries have a lower rate of ovarian cancer, which may have some kind of connection with exposure to Vitamin D.

Other factors that have been investigated, such as talc use, asbestos exposure, high dietary fat content, and childhood mumps infection, are controversial and have not been definitively proven.

"Associations were also found between alcohol consumption and cancers of the ovary and prostate, but only for 50 g and 100 g a day."

Although 20% to 25% of all benign and malignant ovarian neoplasms are of germ cell origin, only about 3% of these tumors are malignant. Germ cell malignancies account for less than 5% of all ovarian cancers in Western countries but they represent up to 15% of ovarian cancers in Asian and black societies, where epithelial ovarian cancers are much less common.

Classification

I. Histology

Ovarian cancer is classified according to the histology of the tumor. Lesions differ significantly in clinical features, management, and prognosis (ICD-O codes provided where available):

➢ Surface epithelial-stromal tumours are the most common and prototypic ovarian cancers. They are thought to originate from the ovarian surface lining, and include serous cystadenocarcinoma (8441/3), and mucinous cystadenocarcinoma (8470/3). The abdominal cavity is lined with the same cells that make up the ovarian surface lining, and it is possible to have cancer begin there, in which case, it is called primary peritoneal cancer. Treatment, however, is basically the same as treatment for ovarian cancer.

➢ Sex cord-stromal tumors include lesions that are hormonally active such as the estrogen-producing granulosa cell tumor (8620/3) and the virilizing Sertoli-Leydig cell tumor or arrhenoblastoma.

➢ Germ cell tumors originate from dysplastic germ material and tend to occur in young women and girls. Lesions include the dysgerminoma (9060/3), a form of the choriocarcinoma (9100/3), and malignant forms of the teratoma (9083/3). Malignant teratoma often contains endodermal sinus tumor (9071/3).

II.History

Ovarian cancer often is primary, but can also be secondary, the result of metastasis from primary cancers elsewhere in the body. For example, from breast cancer, or from gastrointestinal cancer (in which case the ovarian cancer is a Krukenberg cancer).

III. Staging

Ovarian cancer staging is by the FIGO staging system and uses information obtained after surgery, which can include a total abdominal hysterectomy, removal of (usually) both ovaries and fallopian tubes, (usually) the omentum, and pelvic (peritoneal) washings for cytology. The AJCC stage is the same as the FIGO stage.

Stage I - limited to one or both ovaries

IA - involves one ovary; capsule intact; no tumor on ovarian surface; no malignant cells in ascites or peritoneal washings

IB - involves both ovaries; capsule intact; no tumor on ovarian surface; negative washings

IC - tumor limited to ovaries with any of the following: capsule ruptured, tumor on ovarian surface, positive washings

Stage II - pelvic extension or implants

IIA - extension or implants onto uterus or fallopian tube; negative washings

IIB - extension or implants onto other pelvic structures; negative washings

IIC - pelvic extension or implants with positive peritoneal washings

Stage III - microscopic peritoneal implants outside of the pelvis; or limited to the pelvis with extension to the small bowel or omentum.

IIIA - microscopic peritoneal metastases beyond pelvis

IIIB - macroscopic peritoneal metastases beyond pelvis less than 2 cm in size

IIIC - peritoneal metastases beyond pelvis > 2 cm or lymph node metastases

Stage IV - distant metastases--in the liver, or outside the peritoneal cavity

* Para-aortic lymph node metastases are considered regional lymph nodes (Stage IIIC).

Symptoms

1. sense of pelvic heaviness

2. vaginal bleeding

3. weight gain or weight loss

4. abnormal menstrual cycles

5. unexplained back pain that worsens over time

6. increased abdominal girth

7. non specific gastrointestinal symptoms:

– vague lower abdominal discomfort

– increased gas

– indigestion

– lack of appetite

– nausea and vomiting

– Bloody stool

– inability to ingest usual volumes of food

– bloating

8. Additional symptoms that may be associated with this disease:

– increased urinary frequency/urgency

– excessive hair growth

– Fluid buildup in the lining around the lungs (Pleural effusions)

– Positive pregnancy readings (in the absence of pregnancy. This is for germ cell tumors only)

Note: There may be no symptoms until late in the disease.

Diagnosis

Ovarian cancer at its early stages(I/II) is difficult to diagnose until it spreads and advances to later stages(III/IV). This is due to the fact that most of the common symptoms are non-specific.

The blood test called CA-125 is useful in differential diagnosis and in follow up of the disease, but it has not been shown to be an effective method to screen for early-stage ovarian cancer and is currently not recommended for this use.

A study funded by the American Cancer Society conducted at the H. Lee Moffitt Cancer Center & Research Institute has found a correlation between high levels of lysophospholipids (a type of fatty acid) with ovarian cancer patients and low levels of lysophospholipids with healthy women. This potential biomarker can be detected by a simple blood test. The blood test was 93% accurate as predictor of ovarian cancer with less than 4% false positives of the 117 women studied.

Current research is looking at ways to combine tumor markers along with other indicators of disease (i.e. radiology and/or symptoms) to improve accuracy. The challenge in such an approach is that the very low population prevelance of ovarian cancer means that even testing with very high sensitivity and specificity will still lead to unacceptable numbers of false positive results. This is exemplified by the recent discovery of proteomic predictors that showed 100% sensitivity and 95% specificity

A pelvic examination, including CT scan, trans-vaginal ultrasound, is also of utility. Physical examination may reveal increased abdominal girth and /or ascites (fluid within the abdominal cavity). Pelvic examination may reveal an ovarian or abdominal mass. The pelvic exam can include a rectovaginal component for better palpation of the ovaries.

Expectations (prognosis)

1. Ovarian cancer has a poor prognosis. It is disproportionately deadly because symptoms are vague and non-specific. More than 60% of patients presenting with this disease already have stage III or stage IV disease, when it has already spread beyond the ovaries.

2. Ovarian cancers shed malignant cells into the naturally occurring fluid within the abdominal cavity. These cells then have the potential to float in this fluid and frequently implant on other abdominal (peritoneal) structures included the uterus, urinary bladder, bowel, and lining of the bowel wall (omentum). These cells can begin forming new tumor growths before cancer is even suspected.

3. More than 50% of women with ovarian cancer are diagnosed in the advanced stages of the disease because no cost-effective screening test for ovarian cancer exists. The five-year survival rate for all stages is only 35% to 38%. If, however, diagnosis is made early in the disease, five-year survival rates can reach 90% to 98%.

Complications

- spread of the cancer to other organs

- progressive function loss of various organs

- ascites (fluid in the abdomen)

- blockage of the intestines

Germ cell ovarian cancer

Germ Cell Ovarian Cancer has a much better prognosis, but is rarer.

Germ cell ovarian cancer is a rare form of ovarian cancer: approximately 5% of ovarian cancers are classified as germ cell. Treatment is often by chemotherapy drugs that are similar to those used in the treatment of testicular cancer.

Germ cell neoplasms arise from the germ cell elements of the ovary and include dysgerminoma, endodermal sinus tumor, embryonal cell carcinoma, choriocarcinoma, teratoma, polyembryona, and mixed germ cell tumors. Unlike the epithelial neoplasms, which tend to occur during the sixth decade of life, this group of tumors tends to occur during the second and third decades and as a group is associated with a better prognosis. Many of these neoplasms produce biologic markers, which can be monitored to assess response to therapy.

Germ cell tumors are derived from the primordial germ cells of the ovary. Whereas malignant germ cell tumors can arise in extragonadal sites, such as the mediastinum and the retroperitoneum, the majority of germ cell tumors arise in the gonad from the undifferentiated germ cells.

Ovarian Germ Cell Tumors can be divided into three major groups:

(1) benign tumors (usually dermoid cysts);

(2) malignant tumors that arise from dermoid cysts;

(3) primitive malignant germ cell tumors including dysgerminoma, immature teratomas, embryonal carcinomas, and choriocarcinoma.

Dysgerminoma of the ovary is the female counterpart of the seminoma in the male. It occurs primarily in young females and accounts for about 30-40% of germ cell tumors. Grossly, the tumor is rather rubbery in consistency, smooth, rounded, and thinly encapsulated, with a brown or grayish-brown color. This neoplasm is unilateral in 85-90% of cases. It is a solid neoplasm, which may contain areas of softening due to degeneration. Histologically, dysgerminoma mimics the pattern seen in the primitive gonad, i.e., it has nests of germ cells that appear as large, rounded cells with central nuclei that contain one or two prominent nucleoli surrounded by undifferentiated stroma. Lymphocytes may invade the stroma and occasionally giant cells are identified. A lymphocytic infiltrate is considered a favorable prognostic indicator.

Endodermal sinus tumor of the ovary, previously called a yolk sac tumor, is the second most common germ cell neoplasm, occurring in approximately 20% of cases.

Symptoms, Signs and Diagnosis

Functional effects of germ cell or stromal tumors include hyperthyroidism, feminization, and virilization. However, benign functional cysts are common in young women; vaginal sonography or reexamination after 6 wk helps differentiate cysts from tumors.

Mature cystic teratoma (dermoid cyst) are the most common germ cell tumors and in this case all tissue is developmentally mature and there is little or no risk of malignancy. Patients may be asymptomatic or present abdomino-pelvic pain or increasing abdominal girth or a palpable abdominal mass.

Dysgerminomas are the most frequent malignant germ cell tumors in young women (80% of cases). They are rarely pure dysgerminomas but are often mixed with other cell types and synciotrophoblastic types secreting hCG.

Endodermal sinus tumor (yolk sac tumor). These are an association of extra-embryonic mesodermal cells and endodermal cells. The mean age at diagnosis is 19 years and the incidence appears to increase with age.

Gonadoblastoma of the ovary is a rare neoplasm composed of nests of germ cells and sex cord derivatives that are surrounded by connective tissue stroma.

Other tumors include embryonic carcinomas consisting of extra-embryonic and embryonic teratoma-type pluripotential cells.

Laboratory Evaluation

When an ovarian malignancy is included in the list of diagnostic possibilities, a limited number of laboratory tests are indicated. A complete blood count (CBC) and serum electrolyte test should be obtained in all patients. Coagulation tests are not indicated in the absence of a suggestive history of bleeding after minor trauma or increased bruisability. Similarly, routine liver function tests are rarely helpful.

The serum hCG level should be measured in any female in whom pregnancy is a possibility. In addition, a serum AFP and lactate dehydrogenase (LDH) should be measured in young girls and adolescents who present with adnexal masses because the younger the patient, the greater the likelihood of a malignant germ cell tumor.

Treatment

In contrast to epithelial ovarian neoplasms, most germ cell neoplasms are early stage at the time of diagnosis. This observation, in conjunction with the low incidence of bilaterality and the young age of most patients, for whom future fertility is an issue, influences the surgical management of this group of neoplasms. For young women with a germ cell neoplasm of the ovary, removal of the involved adnexa with preservation of the normal-appearing contralateral adnexa and uterus is generally advocated. In view of the low incidence of bilaterality, biopsy or bivalving the contralateral ovary is not recommended because of the risk of peritubal and periovarian adhesions. Complete surgical staging of germ cell neoplasms is the same as for epithelial ovarian neoplasms and should be performed in all cases.

Most patients with advanced-stage germ cell malignancies or high-risk early-stage disease can be cured with combination chemotherapy. Bleomycin, etoposide, and cisplatin are most commonly used.

Radiation Therapy

With respect to germ cell neoplasms, radiation therapy has been used successfully in the treatment of patients with dysgerminoma.

Lecture 17

Uterine cancer

Uterine cancer is the most common cancer of the female reproductive system. The uterus is the female reproductive organ in which a baby grows if a woman becomes pregnant. The uterus consists of three main parts, the cervix is the lower portion of the uterus, the broad middle part is the corpus or body, and the dome-shaped top of the uterus is the fundus. When a woman develops uterine cancer, a tumor is formed on her uterus of abnormal or old cells and can either be benign or malignant.

Types

There are two different types of uterine cancer; the most common form begins in the lining of the uterus, also known as the endometrium. This form of uterine cancer can also be called endometrial cancer, or cancer of the uterus. The other, less common form of uterine cancer, is uterine sarcoma, and this is when the cancer develops in the outer layer of muscle tissue, myometrium, of the uterus.

Risk factors

- The ovaries in a woman’s reproductive system produce estrogen and progesterone. The balances of these two hormones changes monthly making the endometrium thicken in case of pregnancy or shed if no pregnancy occurs. When these hormones shift towards more estrogen, stimulating the growth of the endometrium, the risk for uterine cancer increases. Uterine cancer has several internal causes usually due to the presence of extra estrogen.

- Women who experience more years of menstruation are at a higher risk of uterine cancer. If menstruation begins before the age of 12 years old and continues into a woman’s 50’s the risk is higher, because the more years of menstruation a woman experiences the more years the endometrium is exposed to estrogen.

- Women who have never experienced pregnancy are at a higher risk, because the body produces more progesterone during pregnancy protecting the endometrium by lowering estrogen levels. Women who have never been pregnant do not receive the benefit of this protection.

- Women who do not experience regular cycles are at an increased risk of uterine cancer. Ovulation is regulated by estrogen. Irregular ovulation or failure to ovulate increases a woman’s lifetime exposure to estrogen.

- Women with Type 2 diabetes or women who are obese are at more risk. These two factors generally go hand in hand, because many people with Type 2 diabetes are obese. Although alone they are each risk factors, obese women with Type 2 diabetes are at an increased risk, because fat tissues sometimes change hormones into estrogen resulting in an increased level of estrogen. Fatty foods can also directly affect estrogen metabolism increasing risk.

- Women who participate in Estrogen-only Replacement Therapy (ERT) (a form of Hormone Replacement Therapy) are at a higher risk because ERT stimulates the growth of the endometrium, placing estrogen alone after menopause.

- Uterine cancer is more prevalent in older women, because it takes several years to develop. 95% of women with uterine cancer are over the age of 40. White women are more likely to develop uterine cancer, but African American women are more like to die from it.

Screening

There are no useful screening tests and/or pelvic exams that detect uterine cancer. The disease is most often diagnosed because a woman shows symptoms of the disease. Signs and symptoms of endometrial cancer include abnormal bleeding, spotting, or other discharges from the vagina. Women who have gone through menopause are especially encouraged to consult a physician if abnormal bleeding, spotting, or discharges occur.

Symptoms

Approximately 90% of women diagnosed with uterine cancer have unusual vaginal bleeding or bleeding after menopause. Most cases of uterine cancer develop in women who have gone through menopause and whose periods have stopped. However, there is a small percentage of cases of women under the age of forty with uterine cancer. Although irregular bleeding may show up in other illnesses such as hyperplasia or other non-cancerous conditions, contact a physician if any irregular bleeding may occur. At first, the bleeding may appear watery, but over time the discharge may contain more and more blood.

Vaginal discharge which doesn’t contain blood may also be a sign of uterine cancer. Just because a woman can’t see the blood in the discharge itself, does not mean that the cancer is not present. In approximately 10% of diagnosed cases, the non-bloody discharge experienced by the patients proved to be cancerous. In any case, any abnormal vaginal discharge should result in the consulting of a physician. Sometimes, uterine cancers may progress into advanced stages before any signs or symptoms are shown.

Additional signs of uterine cancer include pelvic pain and/or weight loss. Although these symptoms do occur, they are usually develop in the later stages of the disease. Medical help should be sought after immediately so that the disease is not allowed to progress any further. The delaying of medical help only decreases the chance of treating the disease successfully.

If a woman has any of the aforementioned symptoms then she is encouraged to see a physician who can then come to a decision as to whether or not cancer is present. The physician will ask for a list of symptoms and her medical family history. If the cancer is there, a woman should then be instructed to visit a gynecologist. Early diagnosis is very important when it comes to cancer of the uterus.

Treatment

There are many different treatments for cancer. Uterine cancer, however, is treated most commonly with a smaller sampling of the possible treatments available for cancer patients. After a diagnosis is received, patients usually begin one or two different forms of therapy. The variety, aggressiveness, and overall length of time in treatment depends entirely on the stage and severity of the cancer and the patient (age, health, plans for the future, etc.). The most common treatments for uterine cancer are surgery, radiation therapy, chemotherapy, and hormone therapy.

Surgery involves having a hysterectomy. Having a simple hysterectomy (removal of the entire uterus) or radical hysterectomy (removal of the uterus, surrounding tissues, and cervix) depends on the case.

The option of radiation therapy involves using high-energy radiation to destroy the cancer cells. The procedure is done outside of the body and is not unlike having an X-ray for a broken limb.

Chemotherapy involves taking a series of drugs (either by mouth or through a vein) to kill the cancer cells. Chemotherapy is most often used when the cancer has spread to other areas of the body.

Hormone therapy is mainly used to treat patients with endometrial stromal sarcomas (A rare sarcoma in which the lesions form multiple foci in the myometrium and in vascular spaces in other sites and the tissue and cells resemble endometrial stroma cells). A progesterone-like hormone drug or a drug which stops the production of estrogen can be used. Hormone therapy, however, is not often used and is still being tested.

Prognosis

The Cancer Society estimates that 41,200 women will be diagnosed with uterine cancer in 2006, and of those 7,350 will die. About 70% of all women diagnosed are between the ages of 45-74. A woman’s chance of developing this cancer through out her life time is about 1 in 38. 500,000 women have been diagnosed and survived this cancer. This cancer is 40% more prominently found in white women, however an African American women who is diagnosed with uterine cancer is twice as likely to die. Doctors say that on average the five-year survival rate is at 84%, and this percentage increases if the cancer is detected in early stages.

Prevention

Generally, uterine cancer is a result of internal factors that cannot be prevented, however, a couple factors may help lower the risk of developing uterine cancer such as: taking hormone therapy with progestin, a history of using birth control pills to regulate cycles, and maintaining a healthy weight.

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